Chronic food restriction (FR) increases behavioral sensitivity to drugs of abuse in animal models and is associated with binge eating, which shares comorbidity with drug abuse, in clinical populations. Previous behavioral, biochemical and molecular studies of this laboratory suggest that FR increases the rewarding and locomotor-activating effects of abused drugs as a result of striatal neuroadaptations. Increases in cell signaling and gene expression in response to d- amphetamine and D-1 dopamine (DA) receptor stimulation have been observed. Of particular interest are increased phosphorylation of the NMDA receptor NR1 subunit, AMPA receptor GluR1 subunit, and upregulation of NMDA receptor-dependent ERK 1/2 MAP kinase and CaM kinase II signaling, CREB phosphorylation, and c-fos and neuropeptide gene expression. Several findings have been obtained that support a schema in which the striatal neuroadaptations are secondary to a decrease in basal DA. Moreover, recent findings suggest that decreased stimulation of one or more receptor tyrosine kinases, -most clearly, TrkB-, in the ventral tegmental area (VTA) may be a triggering condition for the striatal and behavioral effects of FR. While the neuroadaptations under investigation may adaptively invigorate goal-directed behavior and facilitate reward-related learning during periods of persistent negative energy balance, they may also be vulnerable to subversion by drugs of abuse and palatable foods in a manner that reinforces maladaptive compulsive behavior. The research proposed in this application is aimed at elucidating midbrain and striatal mechanisms involved in the increased behavioral responsiveness of FR rats to drugs of abuse. Chronic food restriction increases behavioral sensitivity to drugs of abuse in animal models and is associated with binge eating, compulsive exercise, and comorbid drug abuse with eating disorders in clinical populations. The proposed preclinical studies will investigate whether changes in trophic factor regulation of midbrain dopamine neuronal function and consequent alterations in interrelated dopamine and glutamate receptor mechanisms in reward-related forebrain regions are involved in the enhanced behavioral sensitivity of food-restricted subjects to drugs of abuse. This work may identify neuroadaptations that normally mediate adaptive changes in behavior during periods of food scarcity but also, under certain circumstances, increase vulnerability to maladaptive forms of goal-directed behavior, including drug abuse.